Alzheimer's and Parkinson's disease therapies in the clinic

Abstract Alzheimer's disease (AD) and Parkinson's disease (PD) are the most prevalent neurodegenerative diseases, affecting millions and costing billions each year in the United States alone. Despite tremendous progress in developing therapeutics that manage the symptoms of these two diseases, the scientific community has yet to develop a treatment that effectively slows down, inhibits, or cures neurodegeneration. To gain a better understanding of the current therapeutic frontier for the treatment of AD and PD, we provide a review on past and present therapeutic strategies for these two major neurodegenerative disorders in the clinical trial process. We briefly recap currently US Food and Drug Administration‐approved therapies, and then explore trends in clinical trials across the variables of therapy mechanism of disease intervention, administration route, use of delivery vehicle, and outcome measures, across the clinical phases over time for “Drug” and “Biologic” therapeutics. We then present the success rate of past clinical trials and analyze the intersections in therapeutic approaches for AD and PD, revealing the shift in clinical trials away from therapies targeting neurotransmitter systems that provide symptomatic relief, and towards anti‐aggregation, anti‐inflammatory, anti‐oxidant, and regeneration strategies that aim to inhibit the root causes of disease progression. We also highlight the evolving distribution of the types of “Biologic” therapies investigated, and the slowly increasing yet still severe under‐utilization of delivery vehicles for AD and PD therapeutics. We then briefly discuss novel preclinical strategies for treating AD and PD. Overall, this review aims to provide a succinct overview of the clinical landscape of AD and PD therapies to better understand the field's therapeutic strategy in the past and the field's evolution in approach to the present, to better inform how to effectively treat AD and PD in the future.

alone, 1,2 placing heavy financial and emotional burdens on patients as well as their caregivers. Between direct medical costs and indirect costs such as caregiver burden and disability income, AD and PD cost around $305 billion and $51.9 billion, respectively, in the United States annually. 2,3 Furthermore, as the population grow and lifespans increase, neurodegenerative diseases will become more widespread. Globally, AD and PD currently afflict around 50 million and 10 million people, respectively, and are projected to increase to 150 million and 12 million people, respectively, by the year 2050. 1,4,5 Despite decades of research and investment, there are no clinically approved therapies that slow down or prevent the progression of these diseases. Instead, available treatments only mitigate symptoms.
However, many experimental therapies have succeeded in preclinical animal models and are currently under investigation in clinical trials.
The US Food and Drug Administration (FDA) made the clinicaltrials.gov database publicly available in 2000 to document and display information about currently ongoing and completed clinical trials. 6 This database is aimed towards helping patients, health care professionals, researchers, and the public easily access clinical studies for any disease. Patients are able to explore and register for clinical trials that involve therapies targeting the health conditions they are facing.
The clinicaltrials.gov database is the largest registry of its kind and contains a comprehensive list of details for each clinical trial including a brief summary of the study as well as a description of the study design, aims and interventions, key outcome measures, and eligibility criteria for the trial. Its scope was expanded greatly in 2007 when all non-phase 1 interventional clinical trials were required to report results and adverse effects to the database. 6 Despite its value to patients seeking entry into specific trials investigating experimental therapies, the clinicaltrials.gov database lacks a concise cumulative display of information for researchers to glean understanding of the current state of the clinical frontier for a given disease or disorder.
To address this limitation, here we report the clinical trial frontier for the two major neurological disorders: Alzheimer's disease and Parkinson's disease. We begin by first summarizing current clinically approved therapies. To gain a better understanding of the clinical landscape of potential upcoming AD and PD treatments, we have sorted through AD and PD clinical trials to succinctly summarize the therapeutic intervention mechanism, administration route, delivery vehicle, and outcome measures of these investigations across clinical phases and therapy types for past and active registered interventional trials. We provide analyses that present the success rate of past clinical trials and highlight the directions and trends in the clinical landscape across past and active clinical trials. We finally close with a critical analysis of clinical intersections in therapeutic intervention strategies and a brief discussion of novel preclinical strategies for these two most prevalent neurodegenerative diseases. This analysis also emphasizes how the field can benefit from more widely adopting advanced drug delivery strategies utilizing delivery vehicles such as nanoparticle or cellular carriers to enhance therapeutic delivery and hence efficacy. The rest of the article is organized as follows. Section 2 details the approved therapies, Section 3 details the methodology followed for selecting the clinical trial data, Section 4 details the clinical landscape of AD therapies, Section 5 details the clinical landscape of PD therapies, Section 6 details the clinical intersections between AD and PD therapies, and Section 7 discusses novel preclinical strategies.
Finally, we conclude the article in Section 8 detailing the future prospects in the field.
2 | CURRENTLY APPROVED THERAPIES 2.1 | Alzheimer's disease AD is the most common neurodegenerative disorder that affects cognitive function, leading to dementia, confusion, and general mental decline. Classic AD symptoms occur due to brain atrophy and disrupted neuronal signaling in areas essential for cognition and memory, such as the hippocampus and cerebral cortex. 7 AD is characterized at the cellular level by the accumulation of two types of insoluble protein aggregates throughout the brain: extracellular amyloid-beta (Aβ) plaques and intraneuronal and extracellular tau neurofibrillary tangles. 8,9 While the cause of AD has not been confirmed, the well-known "amyloid hypothesis" theorizes that these Aβ aggregates play the primary role in the pathogenesis and progression of AD. 10,11 However, there is growing concern that the field should move beyond the "amyloid hypothesis" and shift focus onto other potential pathogenesis hypotheses. 12 Still, the "amyloid hypothesis" is not yet ruled out, with potential clinical failures attributed to administering therapies too late in AD development to elicit any therapeutic effect. 13 For example, the A4 study coordinated by the University of Southern California's Alzheimer's Therapeutic Research Institute seeks to preemptively treat older individuals at risk of AD with Aβ aggregate-reducing therapies to determine whether proactive treatment prevents AD development. 14 While AD is extensively researched, much remains to be discovered about this clinically devastating and biologically complex disease.  Table 1 lists the specific approved therapies. Several therapies have been approved by the FDA to relieve the symptoms, but not progression of AD. The main limitation of these symptomatic therapies is their inability to slow, stop, or reverses the progression of the disease. These therapies include the acetylcholinesterase inhibitors galantamine hydrobromide (Razadyne, approved in 2001), donepezil hydrochloride (Aricept, approved in 2006), and rivastigmine tartrate (Exelon, approved in 2007), and previously tacrine hydrochloride (Cognex, approved in 1993), which was withdrawn in 2013 due to hepatotoxicity. 15 These therapies manage symptoms of dementia and mental decline via preserving acetylcholine (ACh) levels in the synaptic gaps between neurons by preventing its degradation by acetylcholinesterase. 15 Memantine hydrochloride (Namenda, approved in 2003) is another FDA-approved symptomatic treatment for AD. 16 Memantine hydrochloride is an N-methyl-D-aspartate receptor (NMDAR) antagonist that aims to prevent excess glutamate from overstimulating neurons and causing damage from excitotoxicity. 16 Suvorexant (Belsomra), originally a dual orexin receptor antagonist used for insomnia, was approved in 2020 to treat sleep disorders in AD. 17 In 2021, Aducanumab (Aduhelm), an anti-Aβ monoclonal antibody, became the first Aβ plaque-reducing therapy for AD to be granted FDA approval. 18 However, the efficacy of aducanumab is highly controversial since phase III clinical trials were inconclusive in demonstrating clinical benefits, namely improvements in cognitive function and reduction of dementia. 18 Patients in one study experienced a reduction in AD-related cognitive decline while those in another study did not experience a statistically significant reduction.
Clinical limitations of aducanumab include the several treatmentemergent adverse events (TEAEs) reported during early phase clinical trials investigating its safety. 19 Totally, 41.3% of patients in the EMERGE and ENGAGE clinical trials experienced amyloid-related imaging abnormalities (ARIA), the most common type of TEAE observed, including brain edema, sulcal effusion, and hemosiderin deposits from brain hemorrhage, and 26% of these patients experienced associated symptoms. 20 All cases of symptomatic ARIA were reported as serious adverse effects. However, no patients were hospitalized due to ARIA, and most ARIA cases resolved within 4-12 weeks. 21 The FDA granted accelerated approval of aducanumab due to its consistent success with reducing Aβ levels in AD patients, suggesting a "reasonable likelihood" for clinical improvement, while requiring phase IV clinical trials to prove clinical benefit by February of 2030. 22 If this deadline is not met, FDA approval for aducanumab will be withdrawn. While the clinical benefit of aducanumab has not yet been verified, its availability on the market is a major milestone for AD therapeutic development as it is the first available drug with the potential to slow the progression of AD. Despite these advancements, the existing therapies available for the treatment of AD, while offering significant improvement in management of AD symptoms, are either disputable in efficacy or restricted to providing solely symptomatic relief. AD patients are yet to gain access to a fully approved drug that can reliably slow or stop the progression of AD. By analyzing data from completed and ongoing AD clinical trials, this study will enable researchers to comprehend the current clinical frontier for AD therapeutic development.

| Parkinson's disease
PD is the second most common neurodegenerative disorder with characteristic motor symptoms including tremor, rigidity, bradykinesia, and postural instability. PD patients may also experience nonmotor symptoms including sleep disturbances, psychotic symptoms, sensory disorders, mood disturbances, and cognitive impairment. PD occurs after the loss of dopaminergic neurons in the pars compacta of the substantia nigra, associated with the presence of intracellular aggregates of misfolded alpha-synuclein. 35,36 The exact cause of PD remains unknown, but several implicated processes include neuroinflammation, 37,38 mitochondrial dysfunction, 39-41 oxidative stress, 42 and defective protein homeostasis. 43,44 Table 1 shows a list of key approved therapies for PD. The most prominent approved treatments for the motor symptoms of PD are medications containing levodopa and carbidopa, such as Sinemet, Paracopa, Rytary, and Duopa. Levodopa is a dopamine precursor, 45 and carbidopa is a dopa-decarboxylase inhibitor that reduces extracerebral metabolism of levodopa before it has crossed the protective blood-brain barrier (BBB), 46 enhancing levodopa brain bioavailability. is an enzyme that breaks down dopamine in the brain. 49

| CLINICAL TRIAL DATA SET ORGANIZATION
All clinical trials analyzed were originally sourced from data available from the clinicaltrials.gov database. We eliminated "observational" trials to focus our analysis on "interventional" trials. Within "interventional" trials, we further eliminated trials that were device-, diagnostic, surgical procedure-, implant-, behavioral-, and radiation-based, concentrating on therapeutic interventions namely drug-and biologicbased therapies. Starting with 2603 AD and 2933 PD clinical trials, we reduced the data set to 1005 AD and 938 PD clinical trials after the aforementioned eliminations. Among these, 57 AD and 40 PD did not report the trial phase, and hence were not included in analyses that broke up trials across phases. Following the convention of clinicaltrials.gov, we grouped therapy types into either "Drug" or "Biologic" with minor adjustments for consistency with the FDA definition of biologics. In addition to cell-and protein-based systems, we allocated antibodies, peptides, proteins, natural products, and microbial products under the "Biologic" classification. Natural products refer to plant extracts that contain a cocktail of molecules, such as ginkgo biloba extract. However, if a single molecule was isolated from a natural source, such as resveratrol or curcumin, we classified it as a small molecule and therefore under the "Drug" classification. Figure 2 displays the total number of clinical trials in each clinical phase as a function of trial completion years and therapeutic type ("Drug" and   Abbreviations: AD, Alzheimer's disease; BBB, blood-brain barrier; NMDA, N-methyl-D-aspartate.

| Therapy mechanisms
intervention, AD therapies mainly targeted the cholinergic system (211), with other therapies targeting the dopaminergic (30), serotonergic (71), GABAergic (7), and norepinephrinergic (5) systems. Cholinergic NTS trials refer to therapies that affect the neurotransmitter ACh. ACh is vital to neuronal signaling involved in several cognitive functions including learning, short-term memory, and attention. 62 Drug therapies targeting the cholinergic system typically aim to increase ACh levels, which are lowered in AD. This leads to some symptomatic relief from the cognitive symptoms of AD. These therapies include acetylcholinesterase inhibitors which stop the enzymemediated breakdown of ACh in the synaptic gaps between neurons, nicotinic acetylcholine receptor α7 agonists, and several other medications designed to increase ACh levels. 62 Also, a large proportion of therapies target the neurotransmitters serotonin and dopamine which are connected to several psychological symptoms of AD including apathy and depression. 63 These other NTS therapies are also aimed towards providing symptomatic relief rather than stopping or slowing the progression of AD.
Anti-aggregation therapies dominate the active clinical trial landscape accounting for 30% of active trials increasing from just 14% of past trials. Anti-aggregation therapies utilize a variety of mechanisms to stop the production, accumulation, and toxicity of hyperphosphorylated neurofibrillary tau tangles and Aβ plaques. 64 These therapies typically aim to increase clearance by targeting Aβ or tau with monoclonal antibodies such as aducanumab, or reduce Aβ production with β-secretase 1 inhibitors such as Verubecestat and Lanabecestat, 65 or γ-secretase inhibitors such as Begacestat, 66 to prevent Aβ plaque formation. A greater proportion of clinical trials target Aβ rather than tau, but the proportion of clinical trials targeting tau is greater for "Drug" trials than "Biologic" trials.
A small percentage (7%) of "Biologic" trials investigate regeneration therapies, mostly consisting of mesenchymal stem cell (MSC) transfusion for promoting neuronal growth and regeneration. We also included the category Multiple for clinical trial therapies that intervened via more than one of the seven approaches. Pleiotropic drugs fall in the category of Multiple as these therapeutics often exert multiple effects in concert, such as ginkgo biloba which has anti-aggregation, anti-oxidant, anti-inflammatory, and cholinergic modulation properties. 67,68 The therapy mechanism Other encompasses all other therapeutic approaches that do not fit within the seven outlined categories. Other therapy mechanisms include drugs that modulate the microbiome, hormonal systems, neurovascular system, or glucose metabolism.
Anti-aggregation approaches have been commonly used in past clinical trials, and have increased in popularity among currently active trials. Anti-aggregation was the most common approach in phase 2, and second most common approach in phase 1 and 3 clinical trials in the past, and is currently the most common therapy mechanism in phase 1 and 2 trials. NTS therapies heavily dominated past clinical trials as the most common approach in phases 1, 2, and 4, but have considerably decreased in numbers among currently active trials, especially for newer phase 1 and 2 investigations. Overall, NTS therapies previously and anti-aggregation therapies presently dominate the majority of clinical trials, with a lower percentage of therapies targeting one or more of the following disease mechanisms: apoptosis, excitotoxicity, inflammation, and oxidative stress.
In AD animal models, Aβ has been shown to induce apoptosis of neurons. 69,70 However, its pro-apoptotic role has not been clearly proven in human studies, and its precise molecular mechanism in promoting apoptosis remains unclear. 71 Additional research on the specific role of the disialoganglioside GD3, a potential target of antiapoptotic therapies, is also needed in order to improve therapeutic strategy. 72 Several anti-apoptotic therapies have shown positive results in early clinical trials, but further investigation is needed to confirm these results. 71 Anti-excitotoxic therapies target NMDARs and their ligand, the excitatory neurotransmitter glutamate. Excitotoxicity occurs when NMDARs are overstimulated, allowing excess sodium and calcium ions to enter the neuron, generating excessive levels of reactive oxygen species (ROS), exhausting ATP stores in attempt to reestablish ionic equilibrium, and ultimately inducing necrosis or apoptosis. 73,74 Many anti-excitotoxic therapies are unable to pass the early stages of clinical trials due to the adverse effects caused by a widespread blocking of NMDAR activity which is essential to normal neuronal function. 75 Successful anti-excitotoxic therapies should block NMDAR overstimulation at injured brain regions without impeding essential NMDAR functioning. 76 For this reason, competitive antagonists of glutamate and glycine are prone to causing TEAEs and are not viable options for AD patients. Some noncompetitive antagonists such as MK-801 act allosterically to block the ion channel, but blockage for an extended period also leads to TEAEs. 77 However, antagonists that must first be activated by an agonist before allosteric binding to NMDARs only block NMDAR channels in conditions of excitotoxicity thus providing clinical benefit without TEAEs. One such antagonist is memantine hydrochloride (Namenda), which was approved by the FDA in 2003. 78 Chronic inflammation can damage brain tissue in AD patients due to excess release of cytokines from overactive microglia, astrocytes, and invading peripheral leukocytes. 79 Aβ activates the complement cascade, releasing anaphylatoxins, increasing levels of amyloid precursor protein (APP), and producing free radicals. 80 Clinical trials investigating anti-inflammatory therapies are complicated by the lack of inflammatory biomarker detection methods to monitor the success of these therapies. Studies on inflammatory markers have produced controversial results due to their inconsistent sampling times and patient populations. 81 Current therapeutic strategies targeting inflammation include reducing the concentration and inhibiting the action of cytokines, and manipulating microglia to phagocytose Aβ plaques. 82 Studies investigating the preventive effect of non-steroidal antiinflammatory drugs on AD have shown mixed results, with naproxen (Aleve) and celecoxib (Celebrex) appearing to increase AD risk. 83 Oxidative stress occurs due to the buildup of ROS and contributes to the development of AD. Anti-oxidant therapies aim to mitigate damage caused by oxidative stress, which is pronounced in brain regions most affected by AD. 84 Although several substances that scavenge ROS have been investigated in AD animal models, most anti-oxidant therapies are unable to significantly lower oxidative stress and have overall shown limited success in human patients. 85 Furthermore, some anti-oxidant therapies such as vitamin E may increase oxidative stress under various conditions. 86 When administered in high dose, anti-oxidant therapies have the potential to disrupt the body's natural anti-oxidant defense system. 87 The majority of clinical trials for anti-oxidant therapies are currently confined to earlier stages and more research is needed to verify clinical benefit for AD patients. 88 In addition to anti-aggregation approaches, alternative therapy     indicating that they are nearing FDA approval or have already been approved for general use. "Biologic" therapies are increasingly becoming popular with protein/peptide-based, cell-based, and antibody therapies leading the way by accounting for 28%, 24%, and 21%, respectively of active "Biologic" therapies (see Section 6 for more details). The majority of "Biologic" therapies remain in Phase 1 and Phase 2 as they are relatively new, and target less-explored mechanisms of PD pathology that are mainly still being evaluated for safety. Table 3 Table A1 and AADC inhibitors that reduce levodopa breakdown, and therapies that act as dopamine agonists of D2 or D1/D5 receptors. Other targeted neurotransmitters include serotonin that is employed by drugs that combat nonmotor symptoms of PD, particularly reduction in sleep quality. 104 ACh has been targeted in therapies aimed at treating motor PD symptoms such as dyskinesia as well as nonmotor symptoms such as overactive bladder. 23 Trials with histamine assess its effect on daytime sleepiness in PD patients. Prodrugs of norepinephrine such as Droxidopa that can cross the protective BBB, are also tested for their effects on motor and nonmotor symptoms of PD. 32 Therapies targeting metabotropic glutamate include NMDAR blockers that have been used to reduce dyskinesia. 32 Adenosine a2a receptor agonists are also being explored for their neuroprotective effects and are being used as add-on therapies to shorten off time for patients on carbidopa/levodopa. 32,105 Therapies that target the neurotransmitter GABA are also tested for their effect on sleep quality and motor symptoms.   105 "Biologic" therapies also targeted NTS, with 50% of these targeting dopamine and the remaining 50% targeting ACh.

| Therapy mechanisms
Overall, there is a clear dominance of NTS therapies across past and active trials. Interestingly, the only exception to this is the active phase 1 trials, which are dominated by Anti-aggregation therapies.
We also see an interesting paradigm shift in the diversity of therapy mechanisms leveraged by "Biologics." Anti-aggregation, NTS, and Anti-inflammatory therapies in phase 1, which were once dominated by small molecule drugs are now completely driven by biologics. The eventual outcome of these promising changes are eagerly awaited.

| Outcome measures
Figures 5d and 6d, respectively, show outcome measure used to determine success of the therapy across active and past trials. Most of the "Biologic" therapies (which tended to be in early clinical trial phases) were being monitored for safety, measuring the occurrence TEAEs, or vital sign abnormalities. "Biologic" therapies in phase 2, mostly NTS and Anti-aggregation therapies, are dominantly evaluated for changes in motor symptoms. In contrast, the more established "Drug" therapies were being evaluated for improvements in motor and nonmotor symptoms, commonly using Movement Disorders Society-Unified Parkinson's Disease Rating Scale scores to evaluate efficacy. Other common outcome measures include drug pharmacokinetics, which is usually obtained via plasma drug concentration measurements in patients at various intervals, daytime sleepiness, which is usually evaluated using the Epworth Sleepiness Scale, and pain intensity, which is usually measured using the Visual Analog Scale. 110 Biochemical outcomes including hematology measures such as basophils to leukocytes ratio, eosinophils to leukocytes ratio, lymphocytes to leukocytes ratio, and reticulocytes to erythrocytes ratio are also utilized in PD trials. . This is also expected from broad clinical trial success rates over the last couple of decades. [116][117][118] However, there are deviations from this expected trend for some other therapy mechanisms for "Drug" and "Biologic" trials. One potential reason for deviations is the limited number of clinical trials with reported results for these other categories. This is especially apparent for categories with 100% success or 100% failure rate, where <5 clinical trials account for the percentile. It is also worth noting a large number of trials also evaluate repurposed FDA-approved drugs, which often enter the clinical gauntlet at phase 2 or higher. This is the reason for the absence of phase 1 data for PD Anti-excitotocity category. Nonetheless, this analysis reveals several interesting trends.

| INTERSECTIONS IN CLINICAL APPROACHES
Anti-aggregation clinical studies for AD exhibit a high failure rate of >80% for "Drug" and "Biologic" candidates. Potential explanations include targeting the wrong pathological substrates, administering treatment too late in disease progression, and other issues as discussed by Mehta et al. 119 Anti-inflammatory "Drug" candidates for both AD and PD exhibited greater than 80% and 100% failure in phase 3, respectively, which may also possibly be attributed to AD/PD treatment window. The lone successful phase 3 trial of an antiinflammatory agent targeting AD is antibiotic Doxycycline, which showed promising results, 120  Cell therapy and Gene therapy "Biologic" therapies have undergone a similar trend. Cell therapy trials increased from 1% to 4% to 11% for AD, and 3% to 4% to 8% for PD, and Gene therapy trials increased from 1% to 0% to 3% for AD, and 1% to 2% to 3% for PD from 2011-2015 to 2016-2020 to present. Interestingly, Natural product "Biologic" therapies exhibited a sharp decrease in percentage after 2005 for AD and after 2020 for PD clinical trials. Proteins/peptides-based "Biologic" therapies (note that antibodies are categorized separately) have also gradually decreased in the total percentage of "Biologic" clinical trials. Besides, the prevalence of exploring Antibody therapeutics against AD, the shifts in distribution of "Biologic" candidates being investigated is largely parallel for both AD and PD. Achieving target site-specific accumulation of therapeutics is cumbersome, especially for neurological diseases given the multiple biological barriers such as the BBB and intraparenchymal diffusion. 125 Advanced drug delivery vehicles of synthetic or biological nature may improve upon previously and currently explored therapeutics to provide greater accumulation in the brain to achieve therapeutic efficacy with reduced peripheral side effects.

| Leveraging drug delivery vehicles for clinical translation
The lack of a carrier severely limits the types of drugs that can cross the BBB, where more than 98% of small molecules and essentially 100% of biologics are incapable of bypassing an intact BBB. 126 Drug delivery vehicles may improve brain targeting and expand the types of therapeutics that can achieve brain accumulation, which is naturally limited to small hydrophobic molecules. 73 increasing the opportunity for brain accumulation. In addition to further extending carrier half-life, 131 carrier surface functionalization with low affinity materials such as polyethylene glycol can also enhance diffusive ability, enabling the therapeutic to achieve a wider volume of distribution. 132 Carrier shape can also affect neurovascular adhesion, as demonstrated by increased brain accumulation of rodshaped compared to spherical nanoparticles. 133,134 Furthermore, many free drugs that manage to cross the BBB are often readily ejected out of the brain parenchyma by several active efflux transporters including the P-glycoprotein, ATP binding cassette, multidrug resistance-associated proteins, and breast cancer resistance proteins (BCRP). 135,136 After entering the brain parenchyma, carriers may shield their drug cargo from efflux transporters expressed on the abluminal brain endothelium, reducing efflux transport out of the brain. Furthermore, cell therapies can deliver therapeutics or themselves act as the therapeutic 137 and capitalize on intrinsic chemotactic capabilities to achieve targeted accumulation at injured brain regions following neuroinflammatory chemokine gradients. 138 One of the challenges in translating drug delivery vehicle strategies to the clinic include an increased number of components for the therapeutic, which increases the regulatory hurdles for FDA approval.
Delivery vehicles may also potentially involve more complexity leading to increased costs for manufacturing, involving multiple biomaterials and synthesis or conjugation steps. Developing cell biologics also entails additional considerations adding to production complexity,  Aβ or tau in AD, 139 and against alpha-synuclein in PD. 140 Beyond conventional antigen/adjuvant strategies, Fessel imagines an mRNA vaccine strategy for AD, where mRNA self-amplifies Aβ production. 141 However, the efficacy and safety, in regards to autoimmunity, increased inflammation, and prematurely causing AD, has yet to be evaluated. 141 With promise of CRISPR/Cas9 intervention in Huntington's disease, there is also exploration of CRISPR application in AD and PD. 142 Another growing field of research is the role of extracellular vesicles (EVs), also known as exosomes or microvesicles depending on size, as biomarkers of disease progression in AD and PD. 146,147 EVs from various donor cell origins are also being explored as potential therapeutics due to their complex roles in cell-to-cell communication, and ability to cross the BBB and carry therapeutic cargo. 148,149 EVs derived from MSCs are of special interest as therapeutic carriers. 150 EVs from human teeth stem cells administered intranasally indeed reduced gait impairments in a 6-hydroxydopamine (6-OHDA) rat model of PD. 151 With the growing burden of AD and PD with no effective cures yet, novelty and innovation in therapeutic mechanism and delivery approaches is crucial to bringing effective treatments for neurodegenerative diseases to market.

| CONCLUSION AND OUTLOOK
Clinicaltrials.gov has a wealth of information for gaining insight into the clinical frontier of any given disease. By meticulously organizing the data for AD and PD clinical trials, we have generated figures that succinctly provide information about these clinical trials across different clinical phases, therapy types, and time. This has enabled the illustration of meaningful trends in clinical trials over the years regarding the therapy mechanism of intervention, distribution of "Biologic" therapies explored, and growth of advanced drug delivery strategies.
Although the scientific community has come a long way in terms of symptomatic management of AD and PD, therapeutic innovation in the field is branching into new directions to tackle root causes of disease progression. Notably, Anti-aggregation therapies are taking over NTS therapies as the most common therapy mechanism. This is expected for AD but is also interestingly concurrently happening for PD. There is also a growing number of AD and PD clinical trials that are utilizing Anti-inflammatory, Anti-oxidant, and Regeneration strategies since 2011. The types of "Biologic" therapies used in the clinical frontier is also changing, with consistent use of Antibody-, reduction of Natural product-, and proteins/peptides-based therapies, and increases in Cell therapy and Gene therapy approaches. There is also a growth in the use of delivery vehicles, although they are still heavily underutilized. Currently, many of the clinical trials investigating alternative therapeutic mechanism targets, types of "Biologic" therapies, and utilization of carriers are currently in phase 1 and 2 trials. The upcoming decades will bring many exciting advances as we witness which clinical trials survive running the clinical trial gauntlet to generate novel effective therapies on the market that can finally inhibit or possibly even cure AD and PD progression.

CONFLICT OF INTEREST
The authors declare that they have no competing interests.

DATA AVAILABILITY STATEMENT
All data generated or analyzed during this study are included in this published article. Anti-aggregation Therapies targeting build of misfolded proteins such as the amyloid beta plaques.
Anti-excitotoxicity Therapies targeting excessive stimulation of neuronal receptors.
Anti-oxidant Therapies targeting imbalance between the neuronal production and clearance of reactive oxygen species.
Anti-apoptotic Therapies targeting programmed cell death.

Administration route
Intracerebral Drug administration directly into the brain including intracisternal and intraventricular injections.

Intradermal
Drug administration via a superficial injection into the dermis.

Transdermal
Drug administration via absorption through the skin including using topical creams and patches.

Intestinal
Drug administration directly into the duodenum or upper jejunum.

Intraglandular
Drug administration directly into the glands including salivary glands. Outcome measures Psychiatric Evaluation of cognitive and behavioral metrics using scales such as the Dementia Severity Rating Scale.

Biochemical
Concentration of biomarkers including enzymes such as glucocerebrosidase and proteins such as amyloid beta.

Pain
Evaluation of pain perception and nociceptive thresholds using tests such as thermotests.

Sleep
Evaluation of sleep quality and daytime sleepiness using metrics such as Epworth Sleepiness Scale and REM Sleep Behavior Disorders severity scale.

Volume
Evaluation of changes in hippocampus and total brain volume.

Motor
Evaluation of changes in movement using metrics such as Movement Disorders Society-Unified Parkinson's Disease Rating Scale.

Pharmacokinetics
Evaluation of drug distribution within the body.

Gastrointestinal
Evaluation of gut health using metrics such as Bristol stool scale and Nepean dyspepsia index.

Fatigue
Evaluation of feeling of tiredness and weakness using metrics such as the Fatigue Severity Scale.